The first genetic mutation that appears to protect against multiple aspects of biological aging in humans has been discovered in an extended family of Old Order Amish living in the vicinity of Berne, Indiana, according to a Northwestern Medicine study published in Science Advances.
An experimental “longevity” drug that recreates the effect of the mutation is now being tested in human trials to see if it provides protection against some aging-related illnesses.
Indiana Amish kindred (immediate family and relatives) with the mutation live more than 10 percent longer and have 10 percent longer telomeres (a protective cap at the end of our chromosomes that is a biological marker of aging) compared to Amish kindred members who don’t have the mutation, reports the new study.
Amish with this mutation also have significantly less diabetes and lower fasting insulin levels. A composite measure that reflects vascular age also is lower — indicative of retained flexibility in blood vessels in the carriers of the mutation — than those who don’t have the mutation, the study found.
These Amish individuals have very low levels of PAI-1 (plasminogen activator inhibitor), a protein that comprises part of a “molecular fingerprint” related to aging or senescence of cells. It was previously known that PAI-1 was related to aging in animals but unclear how it affected aging in humans.
“The findings astonished us because of the consistency of the anti-aging benefits across multiple body systems,” said lead author Dr. Douglas Vaughan, the Irving S. Cutter Professor and Chair of Medicine at Northwestern Medicine.
“For the first time we are seeing a molecular marker of aging (telomere length), a metabolic marker of aging (fasting insulin levels) and a cardiovascular marker of aging (blood pressure and blood vessel stiffness) all tracking in the same direction in that these individuals were generally protected from age-related changes,” said Dr. Vaughan, who has been studying PAI-1 for almost 30 years. “That played out in them having a longer lifespan. Not only do they live longer, they live healthier. It’s a desirable form of longevity. It’s their ‘health span.’”
Northwestern has partnered with Tohoku University in Japan in the development and testing of an oral drug, TM5614, that inhibits the action of PAI-1. The drug has already been tested in a phase 1 trial in Japan and is now in phase 2 trials there. Northwestern will apply for FDA approval to start an early phase trial in the U.S., possibly to begin within the next six months.
The proposed Northwestern trial will investigate the effects of the new drug on insulin sensitivity on individuals with type 2 diabetes and obesity because of the mutation’s effect on insulin levels in the Amish.
In the new study, Northwestern scientists looked at individuals who had one mutant copy of the gene, rendering their level of PAI-1 about half the level of kindred with two normal copies.
Those carriers of the gene mutation had nearly 30 percent lower fasting insulin levels and were completely protected from diabetes.
“We were definitely surprised,” Dr. Vaughan said. “Even when we analyze it factoring for their relatedness, the mutation is still an important predictor of whether they’ll get diabetes.”
He said 7 percent of the kindred with two normal copies of the gene have diabetes, so out of the 177 Amish participants in the study, he would expect three or four of the carriers of the single mutant gene to have the disease as well.
The scientists also saw an improvement in a group of cardiovascular measures ― lower blood pressure and more flexible blood vessels ― that change with age. The improvement did not reach statistical significance, but the carriers of the mutant gene have a younger appearing cardiovascular system, Dr. Vaughan said. In particular, individuals in the oldest third of the group have a reduced pulse pressure, indicative of more flexible arteries.
Cognitive testing will be part of future measurements for the study. Experimental data in mice shows lower levels of PAI-1 can protect against Alzheimer’s-like pathology.
“We hope to be able to revisit them regularly and do additional testing to look at the velocity of aging in this kindred and unearth more details about the protective effect of this mutation,” Dr. Vaughan said.